State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Sci Transl Med. 2021 Jan 6;13(575). doi: 10.1126/scitranslmed.abd2655.
Understanding the genetic and epigenetic bases of cellular senescence is instrumental in developing interventions to slow aging. We performed genome-wide CRISPR-Cas9-based screens using two types of human mesenchymal precursor cells (hMPCs) exhibiting accelerated senescence. The hMPCs were derived from human embryonic stem cells carrying the pathogenic mutations that cause the accelerated aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome. Genes whose deficiency alleviated cellular senescence were identified, including , a histone acetyltransferase, which ranked as a top hit in both progeroid hMPC models. Inactivation of KAT7 decreased histone H3 lysine 14 acetylation, repressed transcription, and alleviated hMPC senescence. Moreover, lentiviral vectors encoding Cas9/sg-, given intravenously, alleviated hepatocyte senescence and liver aging and extended life span in physiologically aged mice as well as progeroid mice that exhibit a premature aging phenotype. CRISPR-Cas9-based genetic screening is a robust method for systematically uncovering senescence genes such as , which may represent a therapeutic target for developing aging interventions.
了解细胞衰老的遗传和表观遗传基础对于开发延缓衰老的干预措施至关重要。我们使用两种表现出加速衰老的人间质前体细胞 (hMPC) 进行了全基因组 CRISPR-Cas9 为基础的筛选。这些 hMPC 源自携带导致加速衰老疾病 Werner 综合征和 Hutchinson-Gilford 早衰综合征的致病突变的人类胚胎干细胞。确定了减轻细胞衰老的基因，包括一个组蛋白乙酰转移酶，它在两种早衰 hMPC 模型中均排名第一。KAT7 的失活降低了组蛋白 H3 赖氨酸 14 的乙酰化，抑制了 转录，并减轻了 hMPC 的衰老。此外，静脉内给予编码 Cas9/sg-的慢病毒载体减轻了肝细胞衰老和肝脏老化，并延长了生理老化小鼠以及表现出过早衰老表型的早衰 小鼠的寿命。基于 CRISPR-Cas9 的遗传筛选是一种系统揭示衰老基因的强大方法，例如 ，它可能代表开发衰老干预措施的治疗靶点。
